Recent studies in our laboratory and others demonstrate that the CDK5 gene or its coactivators is amplified in a majority of human pancreatic cancers, expressed in all pancreatic cancer cell lines tested and that CDK5 activity increases as a consequence of the action of mutant k-Ras, which in turn enhaces pancreatic cancer cell growth, invasion and metastasis. We present evidence that the inhibition of CDK5 with a 3, 5- disubstituted pyrazole significantly reduces tumor size, metastasis, and vascularization of pancreatic tumors growing as xenografts in nude mice. We propose to study the effects of CDK5 inhibition on pancreatic adenocarcinoma progression in two distinct mouse models that recapitulate the human disease as it progresses from pancreatitis to PanIN lesions and from PanIN formation through metastasis. This study will focus on inhibiting CDK5 alone during early disease development and evaluate the therapeutic capacity of inhibiting CDK5 in later disease progression, using the inhibitor and Gemcitabine-Abraxane. A second benefit of inhibiting CDK5 is that it reduces pain, given its role in nociceptive signaling. Consequently, we will also undertake preclinical studies to determine if CDK5 inhibition blocks pain associated with pancreatitis and tumor growth. We will also undertake a Phase I human clinical trials that evaluate the clinical utility of inhibiting CDK5 in advanced pancreatic cancer patients that have failed other therapy options. In the longer term these studies may enable Phase II clinical trials for treateing pancreatitis and pancreatic cancer. We will also undertake parallel drug design studies to develop next-generation molecules that improve targeting of CDK5 in pancreatic cancer patients.